Outcomes in Randomized Controlled Trials in Pain: A Proposed Responder Analysis Vibeke Strand, MD Biopharmaceutical Consultant Clinical Professor, Division of Immunology, Stanford University Vibeke Strand, MD Biopharmaceutical Consultant Clinical Professor, Division of Immunology, Stanford University

Responder Analyses have Face and Content Validity Allow assessment of multiple domains Could better categorize analgesics Facilitate comparison of efficacy across: Products Heterogeneous populations, and Multiple disease indications May lead to tiered approach to label indications Precedent: ACR Responder Index in RA Allow assessment of multiple domains Could better categorize analgesics Facilitate comparison of efficacy across: Products Heterogeneous populations, and Multiple disease indications May lead to tiered approach to label indications Precedent: ACR Responder Index in RA

ACR Response Criteria used in RA RCTs Require ≥20% improvement in 5 of 7 measures: Tender Joint Count and Swollen Joint Count and 3 of the following 5: MD Global Physical function: HAQ Pain by VAS Patient Global ESR and/or CRP Require ≥20% improvement in 5 of 7 measures: Tender Joint Count and Swollen Joint Count and 3 of the following 5: MD Global Physical function: HAQ Pain by VAS Patient Global ESR and/or CRP

Strength of Rheumatoid Arthritis Guidance Document Tricenter agreement; Proven track record  6 products! Tiered Label Indications: Improvement in Signs and Symptoms By ACR Response Criteria At 6 or 12 months Inhibition of Radiographic Progression Sharp Scores [erosions + JSN] At 12 months Improvement in physical function and HRQOL HAQ and SF-36 Over 2-5 years May be achieved in a single protocol using prespecified outcome criteria and Hochberg analysis Tricenter agreement; Proven track record  6 products! Tiered Label Indications: Improvement in Signs and Symptoms By ACR Response Criteria At 6 or 12 months Inhibition of Radiographic Progression Sharp Scores [erosions + JSN] At 12 months Improvement in physical function and HRQOL HAQ and SF-36 Over 2-5 years May be achieved in a single protocol using prespecified outcome criteria and Hochberg analysis

Appropriate Domains for Inclusion in RCTs in Chronic Pain Based on a Breakout Session at the Jointly Sponsored FDA / NIH Workshop in May 2002 Definition for the Workshop: RCTs of ≥ 3 months duration; In patients with pain of > 3 months duration, regardless of underlying cause Based on a Breakout Session at the Jointly Sponsored FDA / NIH Workshop in May 2002 Definition for the Workshop: RCTs of ≥ 3 months duration; In patients with pain of > 3 months duration, regardless of underlying cause

Examples of Chronic Pain Indications Musculoskeletal RA OA Low Back Pain Fibromyalgia Neuropathic Diabetic Neuropathy Post Herpetic Neuralgia Trigeminal Neuropathy Cancer Pain [not necessarily >3 months] Rapidly progressive disease Adjust intervention as disease progresses Musculoskeletal RA OA Low Back Pain Fibromyalgia Neuropathic Diabetic Neuropathy Post Herpetic Neuralgia Trigeminal Neuropathy Cancer Pain [not necessarily >3 months] Rapidly progressive disease Adjust intervention as disease progresses

Proposed Domains for Chronic Pain To Be Selected: Regardless of clinical indication Consider available instruments; whether or not Validated in pain or specific clinical indications Previously used in RCTs in Pain Disease specific or generic Strength of choices based on multiple available instruments and prior clinical experience To Be Selected: Regardless of clinical indication Consider available instruments; whether or not Validated in pain or specific clinical indications Previously used in RCTs in Pain Disease specific or generic Strength of choices based on multiple available instruments and prior clinical experience

Proposed Domains for Chronic Pain PAIN: brief, ongoing; allodynia “Need multiple measures of pain” Patient global assessment Rescue medications Time to treatment failure Suffering Pain relief Disease specific measure of improvement / physical function Health related quality of life [HRQOL] Patient global assessment AEs; and how perceived by the patient Damage: irreversible due to disease or its Rx Economics PAIN: brief, ongoing; allodynia “Need multiple measures of pain” Patient global assessment Rescue medications Time to treatment failure Suffering Pain relief Disease specific measure of improvement / physical function Health related quality of life [HRQOL] Patient global assessment AEs; and how perceived by the patient Damage: irreversible due to disease or its Rx Economics

Appropriate Domains for Chronic Pain Final Vote PAIN: unanimous: 28 Physical function / disease specific measure: 27 HRQOL: 24 Patient Global: 15 AEs: 11 This represents a “core set” of minimum required outcome domains to be assessed. Others, specific to the underlying disease process or the clinical indication, may be added as secondary endpoints….. PAIN: unanimous: 28 Physical function / disease specific measure: 27 HRQOL: 24 Patient Global: 15 AEs: 11 This represents a “core set” of minimum required outcome domains to be assessed. Others, specific to the underlying disease process or the clinical indication, may be added as secondary endpoints…..

Goal: Define Improvement Multidimensionally Separate experience of pain itself, from: Functional Impairments and Disability Which may / may not ensue Separate ‘physical impairment’ from ‘disability’ Utilize individual responder analyses Utilize disease ‘specific’ or ‘relevant’, as well as generic measures of HRQOL

Functional Limitations ?? Disability “In the eyes of the beholder” Age, Gender Appropriate Work v Family / Social Limitations Do NOT Necessarily Imply Disability IMPAIRMENT Due to Pain &/or Structural Alterations

Measures for Chronic Pain: Patient Global Assessment of Treatment Intervention “In all the ways your pain affects you, including its treatment, how are you doing today?” Transition question Utilities: EuroQOL or EQ5D Health Utility Index: HUI “In all the ways your pain affects you, including its treatment, how are you doing today?” Transition question Utilities: EuroQOL or EQ5D Health Utility Index: HUI

Minimum Clinically Important Differences [MCID] Degree of improvement in various outcome measures Perceptible to patients Considered clinically important / meaningful Defined by patient query, delphi technique OMERACT: 33-36% improvement; 18% > placebo Demonstrated by statistical correlations with clinical responses in RCTs; patient global assessments Determination of proportion of patients with clinically important improvement provides a more interpretable result with direct clinical implications Degree of improvement in various outcome measures Perceptible to patients Considered clinically important / meaningful Defined by patient query, delphi technique OMERACT: 33-36% improvement; 18% > placebo Demonstrated by statistical correlations with clinical responses in RCTs; patient global assessments Determination of proportion of patients with clinically important improvement provides a more interpretable result with direct clinical implications

Consistency of MCID Values Changes in disease specific or ‘relevant’ measures of function / HRQOL related to ‘much’ or ‘very much’ improvement in patient global assessment Changes in generic measures of HRQOL related to improvements in patient global assessment Consistent high correlations between disease specific and generic measures of HRQOL MCID values consistent. Examples: OA RA FM

Measures of Chronic Pain

Measures of Chronic Pain: PAIN Numeric Pain Intensity Scale VAS or Faces or graphic scales: anchor VAS Verbal rating scales: Likert or VAS Brief Pain Inventory - BPI McGill Pain Questionnaire – MPQ Chronic Pain Coping Inventory - CPCI West Haven-Yale Multidimensional Pain Inventory – MPI ASA Nine Outcomes Measures Treatment Outcomes in Pain Survey - TOPS Numeric Pain Intensity Scale VAS or Faces or graphic scales: anchor VAS Verbal rating scales: Likert or VAS Brief Pain Inventory - BPI McGill Pain Questionnaire – MPQ Chronic Pain Coping Inventory - CPCI West Haven-Yale Multidimensional Pain Inventory – MPI ASA Nine Outcomes Measures Treatment Outcomes in Pain Survey - TOPS

Faces Rating Scale Pain Rating Scale

MCID: Pain Intensity Numerical Rating Scale v. Patient Global Assessment of Change 10 placebo RCTs of Pregabalin in: Diabetic neuropathy, Postherpetic neuralgia, LBP, Fibromyalgia and OA Relationship of “much”, “very much” improved in PGIC [LIkert 5] to PI-NRS [10 points] Reduction of 30% or 2 points in Pain Intensity [PI-NRS] = MCID Regardless of Baseline pain or disease state Farrar et al: Pain 2001; 94:

Measures of Physical Function &/or HRQOL Chronic PAIN Brief Pain Inventory – BPI: cancer HRQOL; not extensively validated in non malignant pain McGill Pain Questionnaire – MPQ: intensity and subjective experience of pain Chronic Pain Coping Inventory – CPCI: coping strategies and level of adjustment Multidimensional Pain Inventory – MPI: HRQOL how psychosocial role functioning affected; omits work-related activity Treatment Outcomes in Pain Survey – TOPS: HRQOL measured longitudinally in individuals Brief Pain Inventory – BPI: cancer HRQOL; not extensively validated in non malignant pain McGill Pain Questionnaire – MPQ: intensity and subjective experience of pain Chronic Pain Coping Inventory – CPCI: coping strategies and level of adjustment Multidimensional Pain Inventory – MPI: HRQOL how psychosocial role functioning affected; omits work-related activity Treatment Outcomes in Pain Survey – TOPS: HRQOL measured longitudinally in individuals

Generic HRQOL Instruments Sickness Impact Profile – SIP implies illness Nottingham Health Profile - NHP Medical Outcomes Survey [MOS] - SF-12 and SF-36 HRQOL in large groups; across disease states Limited assessment of UE, facial pain; Poor differentiation of LBP v upper body pain WHO Quality of Life Instrument - WHOQOL-100 Newer instrument EuroQOL or EQ5D widely used in EU Quality of Well Being - QWB Sickness Impact Profile – SIP implies illness Nottingham Health Profile - NHP Medical Outcomes Survey [MOS] - SF-12 and SF-36 HRQOL in large groups; across disease states Limited assessment of UE, facial pain; Poor differentiation of LBP v upper body pain WHO Quality of Life Instrument - WHOQOL-100 Newer instrument EuroQOL or EQ5D widely used in EU Quality of Well Being - QWB

Disease Specific [‘Relevant’] Measures of Physical Function &/or HRQOL

Disease Specific Measures: Physical Function &/or HRQOL Rheumatoid Arthritis:HAQ, MHAQ, MDHAQ AIMS, AIMS-2 MACTAR, PET Osteoarthritis: WOMAC Harris Hip Score HSS Knee Score and Knee Society Score Ankle OA Score AOFAS hind-, mid- and fore-foot scores LBP: Roland-Morris Oswestry Disability Questionnaire Geriatrics: Katz Index of Independence in ADLs HAQ Cancer: Functional Living Index, Cancer: FLIC Functional Assessment of Cancer Therapy: FACT Rheumatoid Arthritis:HAQ, MHAQ, MDHAQ AIMS, AIMS-2 MACTAR, PET Osteoarthritis: WOMAC Harris Hip Score HSS Knee Score and Knee Society Score Ankle OA Score AOFAS hind-, mid- and fore-foot scores LBP: Roland-Morris Oswestry Disability Questionnaire Geriatrics: Katz Index of Independence in ADLs HAQ Cancer: Functional Living Index, Cancer: FLIC Functional Assessment of Cancer Therapy: FACT

EXAMPLE: Rheumatoid Arthritis: Disease Specific Measures of Physical Function &/or HRQOL

Health Assessment Questionnaire - HAQ Widely accepted, validated, rheumatology-specific instrument to assess physical function in RA Gold Standard: OMERACT/FDA Guidance 20 questions covering 8 types of activities Dressing + Grooming; Arising; Eating; Walking; Hygiene; Reaching; Gripping, ADLs HAQ Disability Index (HAQ DI) Scores the worst items within each scale Based on use of aids and devices Other, shorter versions equally useful: MHAQ, MDHAQ Widely accepted, validated, rheumatology-specific instrument to assess physical function in RA Gold Standard: OMERACT/FDA Guidance 20 questions covering 8 types of activities Dressing + Grooming; Arising; Eating; Walking; Hygiene; Reaching; Gripping, ADLs HAQ Disability Index (HAQ DI) Scores the worst items within each scale Based on use of aids and devices Other, shorter versions equally useful: MHAQ, MDHAQ

SF-36: Short Form 36 Health Survey Validated, widely used generic measure of HRQOL 8 Domains scored ; age, gender adjusted norms Designed to evaluate health status of large groups Doesn’t separate work limitations v everyday activity Summary Scores: Normative based (Mean: 50, SD: 10) Physical Component: PCS –Impact of physical fxn impairment / disability Mental Component: MCS –Impact of mental affect, pain symptoms Change evident within 4 weeks Validated, widely used generic measure of HRQOL 8 Domains scored ; age, gender adjusted norms Designed to evaluate health status of large groups Doesn’t separate work limitations v everyday activity Summary Scores: Normative based (Mean: 50, SD: 10) Physical Component: PCS –Impact of physical fxn impairment / disability Mental Component: MCS –Impact of mental affect, pain symptoms Change evident within 4 weeks

Physical component Mental component Physical function Role physical Bodily pain General health Vitality Social function Role emotion Mental health SF-36 Two-Component Model

1 Guzman et al. Arth Rheum. 1996; 39: Kosinski et al. Arth Rheum. 2000; 43: Redelmeier et al. Arch Intern Med. 1993; 153: Wells et al. J Rheumatol. 1993; 20: Kosinski et al. Arth Rheum. 2000; 43:S140 6 Samsa et al. Pharmacoeconomics. 1999; 15: Thumboo et al. J Rheumatol. 1999; 26: Minimum Clinically Important Differences [MCID] HAQ DI –0.22 SF-36 2, points PCS/MCS mean 50 ± points HAQ DI –0.22 SF-36 2, points PCS/MCS mean 50 ± points ScoreDirectionMCID Range of ScoringLiterature ScoreDirectionMCID Range of ScoringLiterature

Mean Improvement in HAQ Disability Index Year-2 Cohort at 24 Months Improvement Worsening Mean Change from Baseline LEFMTX US301MN302/304 SSZ MN301/303/305 *LEF vs MTX; p= * (248) (273) (51)(46) (97) (101)

Mean Improvement through Week 102 ATTRACT: HAQ Disability Index Mean Improvement through Week 102 MTX + Placebo 3 mg/kg q8w 3 mg/kg q8w 3 mg/kg q4w 3 mg/kg q4w 10 mg/kg q8w 10 mg/kg q8w 10 mg/kg q4w 10 mg/kg q4w < p-value vs. MTX + Placebo All infliximab All infliximab Mean improvement

ERA: Improvement in HAQ Disability Index at 24 months > 0.5 Improvement > 1.0 Improvement % Patients % 55%* 25% 29% *p<.001 Etanercept 25 mg Methotrexate 20 mg Etanercept 25 mg Methotrexate 20 mg 80 Baseline:

US 301: Baseline SF-36 Scores US Norms vs US301 Population 0 Physical Function Role Physical Bodily Pain General Health Perception VitalitySocial Function Role Emotion Mental Health Study US301 PopulationUS Norms (A/S Adjusted)

PBO (n=101) LEF (n=157) MTX (n=162) *LEF vs PBO p<0.05 † LEF vs MTX p<0.05 US301: Mean Improvement in SF-36 Domains ITT Cohort at 12 Months PhysicalRoleBodilyGeneralVitalitySocialRoleMental FunctionPhysicalPainHealthFunctionEmotionHealth Perception * * * * * † † Improvement Worsening Mean Change from Baseline

US301: Mean Improvement in SF-36: Year-2 Cohorts Leflunomide and Methotrexate Better Mean Scores PhysicalRoleBodilyGeneralVitalitySocialRoleMental FunctionPhysicalPainHealthFunctionEmotionHealth Perception US Norms (A/S Adjusted) Baseline Year-2 Cohort

US301: Mean Improvement in SF-36: Year-2 Cohorts Leflunomide and Methotrexate Better Mean Scores PhysicalRoleBodilyGeneralVitalitySocialRoleMental FunctionPhysicalPainHealthFunctionEmotionHealth Perception LEF 24 Months (n = 93) MTX 24 Months (n = 89) US Norms (A/S Adjusted) Baseline Year-2 Cohort

ATTRACT: Mean Improvement in SF-36 Week 54: Physical Domains MTX Control 3 mg/kg q8 Wks 3 mg/kg q4 Wks 10 mg/kg q8 Wks 10 mg/kg q4 Wks 0.035< MTX Control 3 mg/kg q8 Wks 3 mg/kg q4 Wks 10 mg/kg q8 Wks 10 mg/kg q4 Wks 0.083< p-value vs. MTX control

Better Mean Scores BaselineMonth 12Month 24 (n=93) PCSMCS US Norm US301: Mean Improvement in PCS and MCS Leflunomide Year-2 Cohort at 12 & 24 Months 2 SDs below US Norm PCS= Physical Component Summary Score MCS=Mental Component Summary Score PCS= Physical Component Summary Score MCS=Mental Component Summary Score

Improvement in SF-36 PCS Week 102 ATTRACT: Median Improvement in SF-36 PCS Week 102 Baseline: 23.9 – 30.8

Improvement in SF-36 PCS ERA: Mean Improvement in SF-36 PCS 12 Months Improvement in SF-36 PCS ERA: Mean Improvement in SF-36 PCS 12 Months MTX (217) 10 mg (208) 25 mg (207) MTX (204) 10 mg (194) 25 mg (198) MTX (199) 10 mg (188) 25 mg ( 193 ) Baseline6 Months12 Months *p < 0.01, 25 mg vs 10 mg Mean Normal Scores US Norm *

MCID Values Consistent in RCTs in RA Improvements in HAQ DI and SF-36 in RA with newly approved therapies are statistically significant; more importantly, CLINICALLY MEANINGFUL MCID values are consistent across agents and patient populations Disease specific [‘relevant’] measure: HAQ Generic measure: SF-36 Improvements in disease specific highly correlated with generic measures Improvements in HAQ DI and SF-36 in RA with newly approved therapies are statistically significant; more importantly, CLINICALLY MEANINGFUL MCID values are consistent across agents and patient populations Disease specific [‘relevant’] measure: HAQ Generic measure: SF-36 Improvements in disease specific highly correlated with generic measures

EXAMPLE Osteoarthritis: Disease Specific Measures of Physical Function &/or HRQOL

Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index Self-administered questionnaire Developed querying patients with hip or knee OA Reflects physical activities most affected by symptoms, disease manifestations Composite score based on 24 questions; subscores: Pain (5 questions) Joint stiffness (2 questions) Physical function (17 questions) Scored by Likert or cm VAS scales Improvement = negative change Self-administered questionnaire Developed querying patients with hip or knee OA Reflects physical activities most affected by symptoms, disease manifestations Composite score based on 24 questions; subscores: Pain (5 questions) Joint stiffness (2 questions) Physical function (17 questions) Scored by Likert or cm VAS scales Improvement = negative change

WOMAC Scores in Osteoarthritis: MCID MCID in WOMAC composite score, Likert scale: 12 wk pivotal OA RCTs with Celecoxib: 10.1 [0 – 89] Pain, Stiffness, Physical Fxn: 2.1, 1.2, 6.5 [0 – 20] [0 – 8] [0 – 61] MCID in WOMAC VAS: Anchoring to Patient Response to Rx [0-4 Likert scale] 6 wk RCTs OA hip, knee; Rofecoxib v Ibuprofen v PL: Pain, Stiffness, Physical Fxn: 9.7, 10, 9.3 mm, VAS 11 mm VAS for Patient Global Assessment MCID in WOMAC composite score, Likert scale: 12 wk pivotal OA RCTs with Celecoxib: 10.1 [0 – 89] Pain, Stiffness, Physical Fxn: 2.1, 1.2, 6.5 [0 – 20] [0 – 8] [0 – 61] MCID in WOMAC VAS: Anchoring to Patient Response to Rx [0-4 Likert scale] 6 wk RCTs OA hip, knee; Rofecoxib v Ibuprofen v PL: Pain, Stiffness, Physical Fxn: 9.7, 10, 9.3 mm, VAS 11 mm VAS for Patient Global Assessment Ehrich et al: JRheum 2000;27: Zhao et al. Pharmacother 1999;19:

Improvement in WOMAC Composite Scores Week 12 from Baseline: Pivotal OA Trials Improved Scores * P <.05 v placebo * * * * * * * * * * * * MCID = 10.1 (SE=0.4) Zhao et al Pharmacother 1999;19:

WOMAC Physical Function Subscale 12 months: Pivotal RCT, OA knee or hip R = randomization P < 0.05 for all groups; treatment response compared with baseline Cannon GW, et al. Arthritis Rheum. 2000;43:978–987. R = randomization P < 0.05 for all groups; treatment response compared with baseline Cannon GW, et al. Arthritis Rheum. 2000;43:978–987. Mean Change (mm) R R Week Rofecoxib 12.5 mg Rofecoxib 25 mg Diclofenac 150 mg Rofecoxib 12.5 mg Rofecoxib 25 mg Diclofenac 150 mg Mean baseline = 69.6 mm MCID = 9.3

PF RPPAINGHP VITALSOCRE MH Mean Improvement in SF-36: All Rofecoxib v Normative Data US Population Improvement Difference between ages and US population. Ware et al 1993

Change in SF-36 Scores at Week 12 from Baseline: Pivotal Trial in OA of knee * * * * * * * * * * * * ** * * * * * * p <.05 v placebo

SF-36 Scores at Week 12 in OA of knee v US Normative Data in year olds

MCID Values Consistent in RCTs in OA Improvements in WOMAC and SF-36 in OA with newly approved therapies are statistically significant; more importantly, CLINICALLY MEANINGFUL MCID values are consistent across agents and patient populations Disease specific measure: WOMAC Generic measure: SF-36 Improvements in disease specific highly correlated with generic measures Improvements in WOMAC and SF-36 in OA with newly approved therapies are statistically significant; more importantly, CLINICALLY MEANINGFUL MCID values are consistent across agents and patient populations Disease specific measure: WOMAC Generic measure: SF-36 Improvements in disease specific highly correlated with generic measures

EXAMPLE Fibromyalgia: Disease Specific Measures of Physical Function &/or HRQOL

Fibromyalgia: Pain, Sleep Disturbance and Fatigue Correlated Consistent relationships between patient reported: Pain Diary – NRS Pain by MPQ – VAS Sleep Quality Diary – NRS Multidimensional Assessment of Fatigue – MAF Numerical rating [NRS] recorded daily visual analog [VAS] scales reported weekly High baseline scores = impaired sleep and much fatigue Low scores in SF-36 RP, BP and Vitality Poor sleep quantity and quality: MOS-Sleep High scores in MAF = Fatigue Higher levels of anxiety than depression: HADS Corbin et al: Arth Rheum 2001; 44:S66-67, S212

EXAMPLE Cancer Pain: Disease Specific Measures of Physical Function &/or HRQOL

Measures of Physical Function &/or HRQOL CANCER Functional Assessment of Cancer Therapy: FACT Linear Analog Self Assessment: LASA Functional Living Index – Cancer: FLIC Quality of Life Index: QLI European Organization for Research and Treatment of Cancer Questionnaire: EORTC Cancer Rehabilitation Evaluation System: CARES Treatment Outcomes in Pain Survey – TOPS Missoula-Vitas Quality of Life Index: MVQLI Functional Assessment of Cancer Therapy: FACT Linear Analog Self Assessment: LASA Functional Living Index – Cancer: FLIC Quality of Life Index: QLI European Organization for Research and Treatment of Cancer Questionnaire: EORTC Cancer Rehabilitation Evaluation System: CARES Treatment Outcomes in Pain Survey – TOPS Missoula-Vitas Quality of Life Index: MVQLI

Measures of Physical Fxn, HRQOL - CANCER Treatment Outcomes in Pain Survey – TOPS Designed as extension of SF-36; HRQOL Tracks responses in individual patients over time Valid in multiple models of chronic pain / multidisciplinary treatment of pain Functional Living Index, Cancer – FLIC Scales for specific patient populations, diseases Functional Assessment of Cancer Therapy – FACT Scales for specific patient populations, diseases 5 subscales generally relevant; Likert scales Linear Analog Self Assessment Scales – LASA Scales for specific patient populations, diseases VAS scales; readily comprehensible, convenient Treatment Outcomes in Pain Survey – TOPS Designed as extension of SF-36; HRQOL Tracks responses in individual patients over time Valid in multiple models of chronic pain / multidisciplinary treatment of pain Functional Living Index, Cancer – FLIC Scales for specific patient populations, diseases Functional Assessment of Cancer Therapy – FACT Scales for specific patient populations, diseases 5 subscales generally relevant; Likert scales Linear Analog Self Assessment Scales – LASA Scales for specific patient populations, diseases VAS scales; readily comprehensible, convenient

Appropriate Domains: Responder Analysis for Chronic Pain PAIN: multiple instruments NRS, VAS or Face Scales Disease specific [‘relevant’] physical fxn / HRQOL: Many instruments; specific to disease state or TOPS when relevant, may add measures of sleep, depression, etc. Generic measure of HRQOL: such as SF-36 facilitate comparisons across treatments, populations, diseases Patient Global Assessment of Risk/Benefit Specific Question, or Health Utility Measure: HUI, EQ5D AEs PAIN: multiple instruments NRS, VAS or Face Scales Disease specific [‘relevant’] physical fxn / HRQOL: Many instruments; specific to disease state or TOPS when relevant, may add measures of sleep, depression, etc. Generic measure of HRQOL: such as SF-36 facilitate comparisons across treatments, populations, diseases Patient Global Assessment of Risk/Benefit Specific Question, or Health Utility Measure: HUI, EQ5D AEs

Appropriate Domains: Responder Analysis for Acute Pain: hours duration PAIN: Brief Pain Inventory – BPI VAS or Faces Rating Scale Numerical Rating Scale – NRS Time to Treatment Failure Rescue Medications Patient Global Assessment of Risk/Benefit AEs ? Necessity for HRQOL Measure in Acute Pain ? PAIN: Brief Pain Inventory – BPI VAS or Faces Rating Scale Numerical Rating Scale – NRS Time to Treatment Failure Rescue Medications Patient Global Assessment of Risk/Benefit AEs ? Necessity for HRQOL Measure in Acute Pain ?

Appropriate Domains: Responder Analysis for Acute Pain of ≥ 2 Weeks Duration PAIN: Brief Pain Inventory – BPI VAS or Faces Rating Scale Numerical Rating Scale – NRS Time to Treatment Failure Rescue Medications Physical function / disease “relevant” measure: According to disease population; indication or TOPS Generic HRQOL: SF-36 well validated Patient Global Assessment of Risk/Benefit: Specific question HUI or EQ5D AEs

MCID: Acute Pain Cancer Related Breakthrough Pain Titration phase: multiple cross-over RCT of oral transmucosal fentanyl citrate 130 treatment [not opioid] naïve patients; 1268 episodes of pain Differences in pain scores between episodes which did, did not yield adequate pain relief MCID: Pain Intensity Difference [PID] 0-10 = 33% Maximum Total Pain Relief [TOTPAR] 60 mins = 33% Absolute PID, Pain Relief [PR], Sum of PID over 60 mins [SPID] = 2 of 5 points in Likert scale Farrar et al: Pain 2000; 88:287-94

Conclusions: Responder Analyses in Pain RCTs Domains consistent for chronic pain and ≥ 2 weeks Minimum number of required domains Assessed by a variety of validated instruments Add other domains as secondary endpoints PAIN: include time to Rx failure; use of rescue meds Chronic Pain [TOPS] or Disease specific [‘relevant’] HRQOL measures available; validated Addition of generic measure of HRQOL important

Conclusions: Responder Analyses in Pain RCTs As with other Responder Analyses could require: Improvement in a majority of domains but NOT ALL Without deterioration in the others Degree of improvement required could be based on MCID values Improvement across multiple domains not closely correlated: Reflects a ROBUST clinical response May add statistical power; decrease sample sizes

That these decisions be evidence based!!!

“Universal Quality of Life Scale“